Antibody-conjugates with improved therapeutic index for targeting HER2 tumours and method for improving therapeutic index of antibody-conjugates

Patent metadata

Field	Value
Publication number	US-11338043-B2
Application number	US-201716076293-A
Country	US
Kind code	B2
Filing date	Feb 8, 2017
Priority date	Feb 8, 2016
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found N that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F1)x-P in the presence of a catalyst, wherein S(F1)x is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q1, x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F1)x moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Q1 capable of reacting with functional group F1 and a target molecule D connected to Q1 via a linker L2 to obtain the antibody-conjugate wherein linker L comprises S—Z3-L2 and wherein Z3 is a connecting group resulting from the reaction between Q1 and F1. The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting HER2-expressing cells.

First claim

The invention claimed is:

1. A method for targeting HER2-expressing cells, comprising administering to a subject in need thereof an antibody-conjugate, comprising an antibody AB connected to a target molecule D via a linker L, wherein the antibody-conjugate is obtainable by:
(i) contacting a glycoprotein comprising 1 or 2 core N-acetylglucosamine moieties with a compound of the formula S(F 1 ) x -P in the presence of a catalyst, wherein S(F 1 ) x is a sugar derivative comprising x functional groups F 1 capable of reacting with a functional group Q 1 , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F 1 ) x moiety to the core-GlcNAc moiety, to obtain a modified antibody according to Formula (24):

wherein S(F 1 ) x and x are as defined above; AB represents an antibody; GlcNAc is N-acetylglucosamine; Fuc is fucose; b is 0 or 1; and y is 1 or 2; and
(ii) reacting the modified antibody with a linker-conjugate comprising a functional group Q 1 capable of reacting with functional group F 1 and a target molecule D connected to Q 1 via a linker L 2 to obtain the antibody-conjugate wherein linker L comprises S—Z 3 -L 2 and wherein Z 3 is a connecting group resulting from the reaction between Q 1 and F 1 ,
wherein the antibody AB is trastuzumab, S(F 1 ) x is connected to the core-GlcNAc linked to amino acid N300, S(F 1 ) x is 6-azido-6-deoxy-N-acetylgalactosamine, Q 1 is according to formula (9q), L 2 is —CH 2 —O—C(O)—NH—S(O) 2 —NH—(CH 2 —CH 2 —O) 2 —C(O)-Val-Cit-PABC- and target molecule D is Ahx-May, wherein Ahx-May is:

and
wherein formula (9q) is

2. The method according to claim 1 , wherein the targeting HER2-expressing cells includes one or more of treating, imaging, diagnosing, preventing the proliferation of, containing and reducing HER2-expressing cells, in particular HER2-expressing tumours.

3. The method according to claim 1 , wherein the subject suffers from a disorder selected from breast cancer, bladder cancer, pancreatic cancer, gastric cancer.

4. The method according to claim 1 , wherein the antibody-conjugate exhibits increased therapeutic index.

5. The method according to claim 4 , wherein the increased therapeutic index is selected from:
(a) increasing the therapeutic efficacy of the antibody-conjugate; and/or
(b) increasing the tolerability of the antibody-conjugate.

6. A method for targeting HER2-expressing cells, comprising administering to a subject in need thereof an antibody-conjugate, comprising an antibody AB connected to a target molecule D via a linker L, wherein the antibody-conjugate is represented by Formula (41):

wherein:
R 33 and R 34 are hydrogen;
nn=1
Y=O
L 2 (D) r =—O—C(O)—NH—S(O) 2 —NH—(CH 2 —CH 2 —O) 2 —C(O)-Val-Cit-PABC-Ahx-May, wherein Ahx-May is:

pp is 0
y is 1 or 2;
Fuc is fucose;
GlcNAc is N-acetylglucosamine, which is linked to amino acid N300;
S is 6-deoxy-N-acetylgalactosaminyl; and
antibody AB is trastuzumab.

7. The method according to claim 6 , wherein the targeting HER2-expressing cells includes one or more of treating, imaging, diagnosing, preventing the proliferation of, containing and reducing HER2-expressing cells, in particular HER2-expressing tumours.

8. The method according to claim 6 , wherein the subject suffers from a disorder selected from breast cancer, bladder cancer, pancreatic cancer, gastric cancer.

9. The method according to claim 6 , wherein the antibody-conjugate exhibits increased therapeutic index.

10. The method according to claim 9 , wherein the increased therapeutic index is selected from:
(a) increasing the therapeutic efficacy of the antibody-conjugate; and/or
(b) increasing the tolerability of the antibody-conjugate.

Assignees

• Synaffix Bv

Inventors

• Van Berkel Sander Sebastiaan
• Verkade Jorge Merijn Mathieu
• Wijdeven Maria Antonia
• Heesbeen Ryan
• Van De Sande Petrus Josephus Jacobus Maria
• Van Geel Remon
• Janssen Brian Maria Gerardus
• Hurkmans Inge Catharina Josephina
• Van Delft Floris Louis

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/68033

  the drug being a maytansine · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title